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1.Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy: Metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic factors, and oxidative stress induce many growth factors and cytokines that are critical in the genesis of diabetic kidney disease.An exciting discovery made by our group has been the elucidation that the fibrogenic cytokine Transforming Growth Factor-beta (TGF-), through its Smad3 signaling pathway, is an etiologic agent in renal hypertrophy and accumulation of mesangial extracellular matrix proteins in diabetes.Neutralizing anti-TGF-antibodies or antisense TGF-1 oligodeoxynucleotides prevent and/or reverse the hypertrophic and profibrotic effects of the diabetes in mice.However, there is limited evidence to support a role for TGF-in the development of albuminuria.Glomerular basement membrane (GBM) thickening with altered matrix composition, a reduction in nephrin protein in the slit diaphragm, podocyte loss from detachment or apoptosis, and foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria.An equally exciting discovery is our recent demonstration that the podocytederived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor, which can act in a novel autocrine signaling mode, is significantly up-regulated in the diabetic state and participates in the development of the podocytopathy, especially the genesis of albuminuria.There is a link between the aforementioned renal manifestations of diabetes and angiotensin Ⅱ, whose local concentration is stimulated by high glucose, glycated proteins, and mechanical stretch.Angiotensin Ⅱ in turn stimulates podocyte-derived VEGF and suppresses nephrin expression, and it also induces mesangial TGF-1 leading to podocyte apoptosis as well as mesangial matrix expansion, thus fostering the development of glomerulosclerosis.